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Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids.
Br J Pharmacol. 2010 Jun; 160(3):669-76.BJ

Abstract

BACKGROUND AND PURPOSE

Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB(1)) receptors was determined.

EXPERIMENTAL APPROACH

Effects of spinal and peripheral administration of nimesulide (1-100 microg per 50 microL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB(1) receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry.

KEY RESULTS

Spinal, but not peripheral, injection of nimesulide (1-100 microg per 50 microL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB(1) receptor antagonist AM251 (1 microg per 50 microL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide.

CONCLUSIONS AND IMPLICATIONS

Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB(1) receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to understand their contribution to COX-2-mediated analgesia.

Authors+Show Affiliations

School of Biomedical Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK. mbxles@nottingham.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20590570

Citation

Staniaszek, L E., et al. "Effects of COX-2 Inhibition On Spinal Nociception: the Role of Endocannabinoids." British Journal of Pharmacology, vol. 160, no. 3, 2010, pp. 669-76.
Staniaszek LE, Norris LM, Kendall DA, et al. Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids. Br J Pharmacol. 2010;160(3):669-76.
Staniaszek, L. E., Norris, L. M., Kendall, D. A., Barrett, D. A., & Chapman, V. (2010). Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids. British Journal of Pharmacology, 160(3), 669-76. https://doi.org/10.1111/j.1476-5381.2010.00703.x
Staniaszek LE, et al. Effects of COX-2 Inhibition On Spinal Nociception: the Role of Endocannabinoids. Br J Pharmacol. 2010;160(3):669-76. PubMed PMID: 20590570.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids. AU - Staniaszek,L E, AU - Norris,L M, AU - Kendall,D A, AU - Barrett,D A, AU - Chapman,V, PY - 2010/7/2/entrez PY - 2010/7/2/pubmed PY - 2010/10/15/medline SP - 669 EP - 76 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 160 IS - 3 N2 - BACKGROUND AND PURPOSE: Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB(1)) receptors was determined. EXPERIMENTAL APPROACH: Effects of spinal and peripheral administration of nimesulide (1-100 microg per 50 microL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB(1) receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry. KEY RESULTS: Spinal, but not peripheral, injection of nimesulide (1-100 microg per 50 microL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB(1) receptor antagonist AM251 (1 microg per 50 microL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide. CONCLUSIONS AND IMPLICATIONS: Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB(1) receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to understand their contribution to COX-2-mediated analgesia. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/20590570/Effects_of_COX_2_inhibition_on_spinal_nociception:_the_role_of_endocannabinoids_ L2 - https://doi.org/10.1111/j.1476-5381.2010.00703.x DB - PRIME DP - Unbound Medicine ER -